Worldwide, approximately 120 million people suffer from diabetes mellitus. Among these, approximately 12 million are type I diabetics, for whom the administration of insulin is the only therapy currently possible. The people affected have a lifelong dependence on insulin injections, as a rule several times per day. Although type 11 diabetes, from which approximately 100 million people suffer, is not in principle accompanied by a lack of insulin, in a large number of cases treatment with insulin is regarded as the most favorable or only possible form of therapy.
With progressing duration of the illness, a large number of the patients suffer from “diabetic late complications”. What is involved here is essentially micro- and macrovascular damage, which depending on the type and extent results in kidney failure, blindness, loss of extremities or an increased risk of cardiovascular diseases.
As a cause, chronically raised blood glucose levels have primarily been held responsible, since even with careful adjustment of the insulin therapy a normal blood glucose profile, as would correspond to physiological regulation, is not achieved (Ward, J. D. (1989) British Medical Bulletin 45, 111–126; Drury, P. L. et al. (1989) British Medical Bulletin 45, 127–147; Kohner, E. M. (1989) British Medical Bulletin 45, 148–173).
In the healthy person, the insulin secretion is closely dependent on the glucose concentration of the blood. Raised glucose levels, as occur after meals, are rapidly compensated by increased release of insulin. In the fasting state, the plasma insulin level falls to a basal value, which suffices to guarantee a continuous supply of insulin-sensitive organs and tissue with glucose. An optimization of the therapy, “intensified insulin therapy”, is today primarily aimed at keeping variations of the blood glucose concentration, especially upward deviations, as low as possible (Bolli, G. B. (1989) Diabetes Res. Clin. Pract. 6, P3–P16; Berger, M. (1989) Diabetes Res. Clin. Pract. 6, P25–P32). This leads to a significant decrease in the occurrence and the progress of diabetic late damage (The Diabetes Control and Complications Trial Research Group (1993) N. Engl. J. Med. 329, 977–986).
From the physiology of insulin secretion, it can be deduced that for an improved, intensified insulin therapy using subcutaneously administered preparations, two insulin preparations having different pharmacodynamics are needed. For the compensation of the blood glucose increase after meals, the insulin must flow in rapidly and may only act for a few hours. For the basal supply, in particular in the night, a preparation should be available which acts for a long time, has no pronounced maximum and only flows in very slowly.
The preparations based on human and animal insulins fulfill the claims of an intensified insulin therapy, however, only to a restricted extent. Rapidly active insulins (old insulins) reach the blood and the site of action too slowly and have an excessively long total duration of action. The result is that the postprandial glucose levels are too high and several hours after the meal the blood glucose falls too far (Kang, S. et al. (1991) Diabetes Care 14, 142–148; Home, P. J. et al. (1989) British Medical Bulletin 45, 92–110; Bolli, G. B. (1989) Diabetes Res. Clin. Pract. 6, P3–P16). The available basal insulins in turn, especially NPH insulins, have too short a duration of action and possess an excessively strongly pronounced maximum.
In addition to the possibility of influencing the profile of action by means of pharmaceutical principles, the aid of genetic engineering today offers the alternative of designing insulin analogs which achieve certain properties such as onset and duration of action on their own due to their structural properties. By means of the use of suitable insulin analogs, an adjustment of the blood glucose which is significantly better and adapted more closely to the natural conditions could therefore be achieved.
Insulin analogs having an accelerated onset of action are described in EP 0 214 826, EP 0 375 437 and EP 0 678 522. EP 0 214 826 relates, inter alia, to substitutions of B27 and B28, but not in combination with the substitution of B3. EP 0 678 522 describes insulin analogs which contain various amino acids, preferably proline, in position B29, but not glutamic acid. EP 0 375 437 comprises insulin analogs having lysine or arginine in B28, which can optionally additionally be modified in B3 and/or A21. In EP 0 885 961 A1, B3-lysine, B29-glutamate human insulin is disclosed as a novel, rapidly acting insulin.
In EP 0 419 504, insulin analogs are disclosed which are protected against chemical modifications by changing asparagine in B3 and at least one further amino acid in the positions A5, A15, A18 or A21. The insulin analogs described here, however, have only one modification in the position B3 and no further modification of the group mentioned. There is no indication that these compounds possess changed pharmacodynamics with the consequence of a more rapid onset of action.
Insulin analogs are analogs of naturally occurring insulins, namely human insulin or animal insulins, which differ by substitution of at least one naturally occurring amino acid residue and/or addition of at least one amino acid residue and/or organic residue of the corresponding, otherwise identical naturally occurring insulin.
The A chain of human insulin has the following amino acid sequence: Gly Ile Val Glu Gln Cys Cys Thr Ser Ile Cys Ser Leu Tyr Gln Leu Glu Asn Tyr Cys Asn (SEQ ID NO 1)
The B chain of human insulin has the following amino acid sequence: Phe Val Asn Gln His Leu Cys Gly Ser His Leu Val Glu Ala Leu Tyr Leu Val Cys Gly Glu Arg Gly Phe Phe Tyr Thr Pro Lys Thr (SEQ ID NO 2).